Dermatology Online Journal

Letter: Tetracycline-induced hepatotoxicity
Candace Glenn BS¹, Steven R Feldman MD PhD^1,2,3
Dermatology Online Journal 17 (12): 14

1. Department of Dermatology
2. Department of Pathology
3. Public Health Sciences
Center for Dermatology Research, Wake Forest School of Medicine, Winston-Salem, North Carolina

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Abstract

BACKGROUND: Tetracycline is a commonly used drug for rosacea and subantimicrobial doses may resolve the disease in many cases. Although this class of antibiotics has been linked to adverse effects, tetracycline is considered a safe drug. It can be associated with hepatotoxicity, but its role in these rare cases is unclear. PURPOSE: To report the case of a patient with rare tetracycline-induced hepatotoxicity. CASE PRESENTATION: A 49-year-old female with a history of multiple prednisone and methotrexate trials for relapsing polychondritis took oral tetracycline for rosacea. She developed facial and extremity swelling, weakness, and fatigue that corresponded with liver function test (LFT) abnormalities including hypoalbuminemia, low total protein, and elevated alkaline phosphatase. Tetracycline was discontinued and rapid resolution of symptoms and LFT abnormalities occurred after cessation of the drug. CONCLUSIONS: The dose-dependency of rare tetracycline hepatotoxicity and the desire to reduce antibiotic resistance may prompt safe, yet effective, subantimicrobial doses for rosacea.

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Introduction

Though the FDA has not approved its use for this indication, tetracycline is a mainstay of treatment for rosacea. Sneddon's randomized double-blind trial first proved its effectiveness in 1966 with improvement of rosacea signs and symptoms in over three-quarters of patients taking tetracycline 500 mg daily versus less than half of those taking placebo [1]. Papulopustular rosacea is the most responsive subtype to tetracycline, though other types may respond moderately as well [2]. Subantimicrobial doses of tetracycline are suitable for treating rosacea and often lead to near complete resolution, indicating that tetracycline's effects on rosacea are not antibacterial [1, 3]. Tetracycline is a favored drug for rosacea because of its oral administration and low cost, factors that strongly affect patient adherence to dermatological therapies.

Although tetracycline is effective for rosacea, its class of antibiotics has potential side effects: gastrointestinal irritation with oral dosing, hypersensitivity syndrome reactions, serum sickness-like reactions, drug-induced lupus, photosensitization, chelation causing discolored teeth, inhibition of protein synthesis causing bone growth retardation, pancreatitis, nephritis, parotitis, and myocarditis [4, 5]. Rarely, tetracycline can be hepatotoxic, but the mechanism is not well understood. We report the case of a patient taking oral tetracycline for rosacea who developed symptomatic hepatotoxicity with liver function test (LFT) abnormalities and rapid resolution after cessation of the drug.

Case report

A 49-year-old woman presented with itching, tingling, and redness of the face. She had a history of relapsing polychondritis of both ears for which she received several trials of prednisone, methotrexate, and antibiotics. A few weeks before presentation, she was tapered off prednisone and then methotrexate. Her past medical history included hypothyroidism, reflux, and a heterozygous thrombin mutation, but she had no history of liver, gallbladder, or kidney disease. She denied use of tobacco products or alcohol. On initial examination, her face was diffusely erythematous with some telangiectasias and acneiform papules on the chin, consistent with papulopustular rosacea. Because of her multiple trials with prednisone, steroid-induced rosacea was considered. The patient's symptoms failed to respond to topical therapies, including 2 percent erythromycin pads, tretinoin 0.025 percent cream, desonide ointment, and Vanicream lotion, and in April 2009 she was started on tetracycline 500 mg twice daily. Her itching and redness improved on tetracycline and it was tapered down and removed 3 months after starting.

After completing another course of prednisone, the patient had a flare of rosacea in May 2010, with worsened erythema, pruritus, and a painful nodule on the right cheek. Tetracycline was reinitiated at a dose of 500 mg three times daily. It was tapered down over several months to 500 mg twice daily as the rosacea symptoms decreased and remained stable. However, she noticed swelling and watering of her eyes for several months and her LFTs showed hypoalbuminemia (3.2) in November 2010. Consistent with worsening hypoalbuminemia, her ankles, feet, and legs also became severely edematous. Other abnormalities became apparent in January 2011, including low total protein and elevated alkaline phosphatase (Table 1). The patient experienced dramatic loss of energy to the point of feeling drained after climbing two flights of stairs and being unable to rise from a squatting position. Thyroid function tests (TFTs) showed hyperthyroidism, thought to be secondary to the hypoalbuminemia with increased active, unbound thyroid hormone. Hashimoto thyroiditis was diagnosed. However, laboratory studies showed elevated thyroid microsomal antibodies and autoimmune disorders were considered as a possible cause of her LFT abnormalities. Workup was negative for antinuclear, SSA-Ro, SSB-La, mitochondrial M2, and small microsomal antibodies, thus decreasing the likelihood of connective tissue disease and autoimmune hepatitis.

Although liver transaminases, bilirubin, and coagulation studies remained within normal limits, other causes of hepatitis and liver dysfunction were tested and ruled out, including: viral hepatitis panel, alpha 1 antitrypsin deficiency, and Wilson disease. Also in February 2011, abdominal ultrasound showed a normal appearance of the liver without evidence of cholelithiasis, cholecystitis, or biliary obstruction. Multiple urinalyses with negative urine protein ruled out nephrotic syndrome as the cause of low albumin and adequate kidney function was confirmed on frequent basic metabolic panels, thus decreasing the likelihood of toxic drug levels from inadequate clearance. With no known hepatotoxic associations, she was continued on all of her other oral medications throughout this time, including: levothyroxine, cholecalciferol, calcium carbonate-vitamin D, multivitamin, hydrochlorothiazide, and Align® Probiotic tablets. In the midst of this, the patient had several abnormal breast biopsies that lead to a double mastectomy in April 2011, so the elevated alkaline phosphatase was concerning for metastatic disease. A whole body bone scan in June 2011 was negative for lytic lesions and liver biopsy in March 2011 showed mild lymphocytic inflammation within the portal tract areas and no other abnormalities.

Having ruled out other causes of LFT abnormalities, the possibility of tetracycline-induced hepatotoxicity was considered. Tetracycline was stopped in June 2011 and her albumin, total protein, and alkaline phosphatase rapidly normalized; normal LFTs returned two weeks after stopping the tetracycline (Table 1). Her fatigue and edema also rapidly resolved. One month after discontinuing tetracycline she was started on a subantimicrobial dose of doxycycline (Oracea® at 40 mg daily) for rosacea and has remained asymptomatic with normal LFTs.

Discussion

Tetracycline has been considered a safe and effective rosacea medication for many years. However, hepatotoxicity is seen with doxycycline or tetracycline, occurring in up to 3 in 100 patients. However, it is uncommon when compared to another potentially hepatotoxic drug, acetaminophen, with 13 in 100 patients developing hepatotoxicity [6]. Toxic hepatitis, acute and subacute necrosis of the liver, and hepatic coma can occur, but are rare. Certain factors increase the risk of tetracycline-induced hepatotoxicity, but our patient did not have any of the obvious ones. These risk factors include large doses of the drug, extended length of treatment, pregnancy or other physiologic change, and severe infection [4, 7, 8]. Metabolism and elimination of tetracycline occur in the liver and kidney and dysfunction of these organs may increase susceptibility to liver complications [8].

Tetracycline-induced hepatotoxicity was initially described in 1951. Deleterious pathological effects on liver cell metabolism manifested as fine droplet fatty metamorphosis and occurred when high doses were administered for long periods of time [4, 7, 9-14]. Parenteral doses greater than 2 gm/day of tetracyclines caused a majority of hepatotoxic events [14]. Our patient also received antimicrobial doses of tetracycline, but she was given only oral formulas not exceeding 1,500 mg daily. Steatosis was not present in her liver biopsy. Because tetracyclines are dependent on biliary excretion, it is recommended that these not be given to patients with preexisting liver disease [11]. Although our patient had no preexisting liver disease, she took methotrexate, another potentially hepatotoxic drug, prior to treatment with tetracycline. There is no evidence, however, of increased hepatic damage in patients taking other hepatotoxic drugs with tetracycline or even in patients with preexisting liver disease [7].

Pregnant women are susceptible to developing hepatic damage when treated with tetracyclines, especially large intravenous doses [7, 10, 12-15]. Physiologic changes of pregnancy are likely responsible for this, but the specific mechanisms that increase susceptibility during pregnancy are unknown. Our patient may have had systemic changes making her more vulnerable to the hepatotoxic effects of tetracycline such as multiple prior courses of immunosuppressants and concomitant autoimmune thyroid disease and breast cancer. In a study of pregnant patients being treated with tetracycline for pyelonephritis, LFTs showed increased free and conjugated bilirubin, serum glutamic oxaloacetic transaminase (SGOT), and alkaline phosphatase [15]. Postmortem examinations in these patients who died from terminal shock revealed fine droplet metamorphosis of liver lobules without inflammation or biliary obstruction. Similarly, elevated alkaline phosphatase without biliary obstruction was seen in our patient, but she did have mild inflammation of the portal triad.

Warning signs of liver damage may include nausea, vomiting, jaundice, wide fluctuations in temperature, azotemia, acidosis, melena, and hematemesis [15]. Our patient did not have any of these symptoms, but she did have fatigue, edema, and weakness that worsened directly with her liver abnormalities. Hepatotoxicity may occur in the absence of obvious risk factors because current and past users are at increased risk of developing hepatotoxicity, despite the dose amount or duration [6]. Whites, like our patient, are the largest ethnic group represented in cases of hepatotoxicity followed by Hawaiian/Pacific Islanders and then African-Americans, thus genetic variability may be linked with susceptibility. In support of this idea, tetracycline produces global changes in hepatic gene expression in mice [16]. This may be significant in fields, like dermatology, in which tetracyclines are prescribed to a variety of patient populations with unpredictable genetic susceptibilities to hepatotoxicity.

Conclusion

We report the case of a patient with a rare manifestation of tetracycline-induced hepatotoxicity. Pregnancy, impaired kidney function, preexisting liver disease, extensive infection, and high doses of the drug are risk factors for tetracycline hepatotoxicity. In the presence of these conditions, a more careful consideration is warranted. Even patients like ours, without obvious risk factors have the potential to develop liver toxicity with antimicrobial doses of the drug. Nevertheless, this is not a reason to discontinue use of an efficacious, inexpensive, and adherence-friendly rosacea medication. Attention to clinical signs of liver disturbance allows abnormalities to be caught and corrected, either by stopping or decreasing the dose of the drug. Because high antibacterial doses of tetracycline are consistently found in cases of hepatoxicity, subantibacterial doses will likely result in fewer cases. Considering the dose-dependency of tetracycline hepatotoxicity and the desire to reduce antibiotic resistance, subantimicrobial doses may be the safest, yet still effective regimen for rosacea.

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